Selection Of A Novel Aptamer Against Vitronectin Using Capillary Electrophoresis And Next Generation Sequencing

Breast cancer (BC) results in ≃40,000 deaths each year in the United States and even among survivors treatment of the disease may have devastating consequences, including increased risk for heart disease and cognitive impairment resulting from the toxic effects of chemotherapy. Aptamer-mediated drug delivery can contribute to improved treatment outcomes through the selective delivery of chemotherapy to BC cells, provided suitable cancer-specific antigens can be identified. We report here the use of capillary electrophoresis in conjunction with next generation sequencing to develop the first vitronectin (VN) binding aptamer (VBA-01; Kd 405 nmol/l, the first aptamer to vitronectin (VN; Kd = 405 nmol/l), a protein that plays an important role in wound healing and that is present at elevated levels in BC tissue and in the blood of BC patients relative to the corresponding nonmalignant tissues. We used VBA-01 to develop DVBA-01, a dimeric aptamer complex, and conjugated doxorubicin (Dox) to DVBA-01 (7:1 ratio) using pH-sensitive, covalent linkages. Dox conjugation enhanced the thermal stability of the complex (60.2 versus 46.5°C) and did not decrease affinity for the VN target. The resulting DVBA-01-Dox complex displayed increased cytotoxicity to MDA-MB-231 BC cells that were cultured on plasticware coated with VN (1.8 × 10⁻⁶mol/l) relative to uncoated plates (2.4 × 10⁻⁶ mol/l), or plates coated with the related protein fibronectin (2.1 × 10⁻⁶ mol/l). The VBA-01 aptamer was evaluated for binding to human BC tissue using immunohistochemistry and displayed tissue specific binding and apparent association with BC cells. In contrast, a monoclonal antibody that preferentially binds to multimeric VN primarily stained extracellular matrix and vessel walls of BC tissue. Our results indicate a strong potential for using VN-targeting aptamers to improve drug delivery to treat BC

Yukawa couplings and masses of non-chiral states for the Standard Model on D6-branes on T6/Z6'

The perturbative leading order open string three-point couplings for the Standard Model with hidden USp(6) on fractional D6-branes on T6/Z6' from arXiv:0806.3039 [hep-th], arXiv:0910.0843 [hep-th] are computed. Physical Yukawa couplings consisting of holomorphic Wilsonian superpotential terms times a non-holomorphic prefactor involving the corresponding classical open string Kaehler metrics are given, and mass terms for all non-chiral matter states are derived. The lepton Yukawa interactions are at leading order flavour diagonal, while the quark sector displays a more intricate pattern of mixings. While N=2 supersymmetric sectors acquire masses via only two D6-brane displacements - which also provide the hierarchies between up- and down-type Yukawas within one quark or lepton generation -, the remaining vector-like states receive masses via perturbative three-point couplings to some Standard Model singlet fields with vevs along flat directions. Couplings to the hidden sector and messengers for supersymmetry breaking are briefly discussed.Comment: 52 pages (including 8p. appendix); 5 figures; 14 tables; v2: discussion in section 4.1.3 extended, footnote 5 added, typos corrected, accepted by JHE

DBI Inflation using a One-Parameter Family of Throat Geometries

We demonstrate the possibility of examining cosmological signatures in the DBI inflation setup using the BGMPZ solution, a one-parameter family of geometries for the warped throat which interpolate between the Maldacena-Nunez and Klebanov-Strassler solutions. The warp factor is determined numerically and subsequently used to calculate cosmological observables including the scalar and tensor spectral indices, for a sample point in the parameter space. As one moves away from the KS solution for the throat the warp factor is qualitatively different, which leads to a significant change for the observables, but also generically increases the non-Gaussianity of the models. We argue that the different models can potentially be differentiated by current and future experiments.Comment: 17 pages, 10 figures; v2: section 4 expanded, references added; v3: typos fixe

Rapidly-Varying Speed of Sound, Scale Invariance and Non-Gaussian Signatures

We show that curvature perturbations acquire a scale invariant spectrum for any constant equation of state, provided the fluid has a suitably time-dependent sound speed. In order for modes to exit the physical horizon, and in order to solve the usual problems of standard big bang cosmology, we argue that the only allowed possibilities are inflationary (albeit not necessarily slow-roll) expansion or ekpyrotic contraction. Non-Gaussianities offer many distinguish features. As usual with a small sound speed, non-Gaussianity can be relatively large, around current sensitivity levels. For DBI-like lagrangians, the amplitude is negative in the inflationary branch, and can be either negative or positive in the ekpyrotic branch. Unlike the power spectrum, the three-point amplitude displays a large tilt that, in the expanding case, peaks on smallest scales. While the shape is predominantly of the equilateral type in the inflationary branch, as in DBI inflation, it is of the local form in the ekpyrotic branch. The tensor spectrum is also generically far from scale invariant. In the contracting case, for instance, tensors are strongly blue tilted, resulting in an unmeasurably small gravity wave amplitude on cosmic microwave background scales.Comment: 41 pages, 12 figures. v4: Few typos in equations (7.39) correcte

D6-branes and torsion

The D6-brane spectrum of type IIA vacua based on twisted tori and RR background fluxes is analyzed. In particular, we compute the torsion factors of the (co)homology groups H_n and describe the effect that they have on D6-brane physics. For instance, the fact that H_3 contains Z_N subgroups explains why RR tadpole conditions are affected by geometric fluxes. In addition, the presence of torsional (co)homology shows why some D6-brane moduli are lifted, and it suggests how the D-brane discretum appears in type IIA flux compactifications. Finally, we give a clear, geometrical understanding of the Freed-Witten anomaly in the present type IIA setup, and discuss its consequences for the construction of semi-realistic flux vacua.Comment: 35 pages, 1 figure. One reference adde

Calibrated cycles and T-duality

For Hitchin's generalised geometries we introduce and analyse the concept of a structured submanifold which encapsulates the classical notion of a calibrated submanifold. Under a suitable integrability condition on the ambient geometry, these generalised calibrated cycles minimise a functional occurring as D-brane energy in type II string theories, involving both so-called NS-NS- and R-R-fields. Further, we investigate the behaviour of calibrated cycles under T-duality and construct non-trivial examples.Comment: 43 pages. v4: formalism and T-duality part considerably expande

Deformations of calibrated D-branes in flux generalized complex manifolds

We study massless deformations of generalized calibrated cycles, which describe, in the language of generalized complex geometry, supersymmetric D-branes in N=1 supersymmetric compactifications with fluxes. We find that the deformations are classified by the first cohomology group of a Lie algebroid canonically associated to the generalized calibrated cycle, seen as a generalized complex submanifold with respect to the integrable generalized complex structure of the bulk. We provide examples in the SU(3) structure case and in a `genuine' generalized complex structure case. We discuss cases of lifting of massless modes due to world-volume fluxes, background fluxes and a generalized complex structure that changes type.Comment: 52 pages, added references, added comment on ellipticity in appendix B, made minor changes according to instructions referee JHE